The overall objective of the proposed study is to delineate the parameters that permit the long-term engraftment and expression of fetal and adult hematopoietic stem cells (HSC) transplanted in utero without cytoablation and without graft-vs-host disease (GVHD). Specifically, we will the sheep as the large animal experimental model to achieve more efficient HSC engraftment by a) determining the optimal concentrations of fetal and adult sheep cells that will result in the most efficient HSC engraftment, b) the effect of upmodulation of HSC homing receptor activity on donor cell engraftment, and c) the role of donor T cell subsets in grafting efficiency and GVHD. Modulation of homing receptor activity and in vitro transduction of autologous HSC will be used to study a) the mechanism(s) underlying the naturally occurring switches in primary sites of hematopoiesis from yolk sac to liver and bone marrow during ontogeny, and b) the role of bone marrow (and liver) in blood cell production during the early prenatal periods. It is hoped that the in utero HSc transplantation procedures developed here will permit the treatment of some lymphohematopoietic disorders in utero before the disease has had a chance to clinically compromise the patient.